Segawa syndrome caused by TH gene mutation and its mechanism

Yilin Wang; Chunmei Wang; Meiyan Liu; Wuhen Xu; Simei Wang; Fang Yuan; Xiaona Luo; Quanmei Xu; Rongrong Yin; Anqi Wang; Miao Guo; Longlong Lin; Chao Wang; Hongyi Cheng; Zhiping Liu; Yuanfeng Zhang; Fanyi Zeng; Jingbin Yan; Yucai Chen

doi:10.3389/fgene.2022.1004307

Segawa syndrome caused by TH gene mutation and its mechanism

Front Genet. 2022 Dec 8:13:1004307. doi: 10.3389/fgene.2022.1004307. eCollection 2022.

Authors

Yilin Wang¹, Chunmei Wang¹, Meiyan Liu¹, Wuhen Xu¹, Simei Wang¹, Fang Yuan¹, Xiaona Luo¹, Quanmei Xu¹, Rongrong Yin¹, Anqi Wang¹, Miao Guo¹, Longlong Lin¹, Chao Wang¹, Hongyi Cheng¹, Zhiping Liu¹, Yuanfeng Zhang¹, Fanyi Zeng², Jingbin Yan², Yucai Chen¹

Affiliations

¹ Department of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China.
² Shanghai Key Laboratory of Embryo and Reproduction Engineering, Key Laboratory of Embryo Molecular Biology of National Health Commission, Shanghai Institute of Medical Genetics, Shanghai Chlidren's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China.

Abstract

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease. The decrease in dopamine caused by tyrosine hydroxylase (TH) gene mutation may lead to dystonia, tremor and severe encephalopathy in children. Although the disease caused by recessive genetic mutation of the tyrosine hydroxylase (TH) gene is rare, we found that the clinical manifestations of seven children with tyrosine hydroxylase gene mutations are similar to dopa-responsive dystonia. To explore the clinical manifestations and possible pathogenesis of the disease, we analyzed the clinical data of seven patients. Next-generation sequencing showed that the TH gene mutation in three children was a reported homozygous mutation (c.698G>A). At the same time, two new mutations of the TH gene were found in other children: c.316_317insCGT, and c.832G>A (p.Ala278Thr). We collected venous blood from four patients with Segawa syndrome and their parents for real-time quantitative polymerase chain reaction analysis of TH gene expression. We predicted the structure and function of proteins on the missense mutation iterative thread assembly refinement (I-TASSER) server and studied the conservation of protein mutation sites. Combined with molecular biology experiments and related literature analysis, the qPCR results of two patients showed that the expression of the TH gene was lower than that in 10 normal controls, and the expression of the TH gene of one mother was lower than the average expression level. We speculated that mutation in the TH gene may clinically manifest by affecting the production of dopamine and catecholamine downstream, which enriches the gene pool of Segawa syndrome. At the same time, the application of levodopa is helpful to the study, diagnosis and treatment of Segawa syndrome.

Keywords: TH tyrosine hydroxylase deficiency; dopa-responsive dystonia; guanosine triphosphate cyclic hydrolase; high-throughput sequencing; tyrosine hydroxylase gene.